Редактирование: ARNT

Aryl hydrocarbon receptor nuclear translocator (ARNT protein) (Class E basic helix-loop-helix protein 2) (bHLHe2) (Dioxin receptor, nuclear translocator) (Hypoxia-inducible factor 1-beta) (HIF-1-beta) (HIF1-beta) [BHLHE2]

==Publications==

{{medline-entry
|title=Loss of [[ARNT]] in skeletal muscle limits muscle regeneration in aging.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33064329
|abstract=The ability of skeletal muscle to regenerate declines significantly with aging. The expression of aryl hydrocarbon receptor nuclear translocator ([[ARNT]]), a critical component of the hypoxia signaling pathway, was less abundant in skeletal muscle of old (23-25 months old) mice. This loss of [[ARNT]] was associated with decreased levels of Notch1 intracellular domain (N1ICD) and impaired regenerative response to injury in comparison to young (2-3 months old) mice. Knockdown of [[ARNT]] in a primary muscle cell line impaired differentiation in vitro. Skeletal muscle-specific [[ARNT]] deletion in young mice resulted in decreased levels of whole muscle N1ICD and limited muscle regeneration. Administration of a systemic hypoxia pathway activator (ML228), which simulates the actions of [[ARNT]], rescued skeletal muscle regeneration in both old and [[ARNT]]-deleted mice. These results suggest that the loss of [[ARNT]] in skeletal muscle is partially responsible for diminished myogenic potential in aging and activation of hypoxia signaling holds promise for rescuing regenerative activity in old muscle.

|keywords=* aging
* hypoxia signaling
* muscle regeneration
|full-text-url=https://sci-hub.do/10.1096/fj.202000761RR
}}
{{medline-entry
|title=[Arylhydrocarbon receptor nuclear translocator ([[ARNT]]) in human skin during aging.]
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32593246
|abstract=The aim of this work was to examine the content of arylhydrocarbon receptor nuclear translocator ([[ARNT]]) in fibroblasts of human dermis from 20 weeks of pregnancy until 85 years old, and defining of a role of [[ARNT]] in age-dependent changes in the number of fibroblasts in the dermis. [[ARNT]], proliferating cells nuclear antigen ([[PCNA]]) were detected with indirect immunohistochemical technique. Results showed that a portion of fibroblasts with positive staining for [[ARNT]] in the dermis is decreased from 20 weeks of pregnancy to 40 years old. Percent of [[ARNT]] positive fibroblasts in dermis is increased sufficiently since 41 year old until 60-85 years old group. A total number and percent of [[PCNA]] positive fibroblasts in dermis decreased with progression of age. Most sufficient age-dependent reduction in a total and [[PCNA]] positive number of dermal fibroblast was observed from antenatal until 40 years of life. Age-related changes in the content of [[ARNT]] in fibroblasts is not associated with an age-related decrease in total number and percent of [[PCNA]] positive fibroblasts the dermis.
|mesh-terms=* Adolescent
* Adult
* Aged
* Aged, 80 and over
* Aging
* Aryl Hydrocarbon Receptor Nuclear Translocator
* Child
* Child, Preschool
* Dermis
* Fetus
* Fibroblasts
* Humans
* Infant
* Infant, Newborn
* Skin
* Skin Aging
* Young Adult
|keywords=* ARNT
* PCNA
* aging
* fibroblasts
* skin

}}
{{medline-entry
|title=The E3 ubiquitin ligase [[STUB1]] attenuates cell senescence by promoting the ubiquitination and degradation of the core circadian regulator BMAL1.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32041778
|abstract=Cell senescence is one of the most important processes determining cell fate and is involved in many pathophysiological conditions, including cancer, neurodegenerative diseases, and other aging-associated diseases. It has recently been discovered that the E3 ubiquitin ligase [[STIP1]] homology and U-box-containing protein 1 ([[STUB1]] or CHIP) is up-regulated during the senescence of human fibroblasts and modulates cell senescence. However, the molecular mechanism underlying [[STUB1]]-controlled senescence is not clear. Here, using affinity purification and MS-based analysis, we discovered that [[STUB1]] binds to brain and muscle [[ARNT]]-like 1 (BMAL1, also called aryl hydrocarbon receptor nuclear translocator-like protein 1 ([[ARNT]]L)). Through biochemical experiments, we confirmed the [[STUB1]]-BMAL1 interaction, identified their interaction domains, and revealed that [[STUB1]] overexpression down-regulates BMAL1 protein levels through [[STUB1]]'s enzymatic activity and that [i][[STUB1]][/i] knockdown increases BMAL1 levels. Further experiments disclosed that [[STUB1]] enhances BMAL1 degradation, which is abolished upon proteasome inhibition. Moreover, we found that [[STUB1]] promotes the formation of Lys-48-linked polyubiquitin chains on BMAL1, facilitating its proteasomal degradation. Interestingly, we also discovered that oxidative stress promotes [[STUB1]] nuclear translocation and enhances its co-localization with BMAL1. [[STUB1]] expression attenuates hydrogen peroxide-induced cell senescence, indicated by a reduced signal in senescence-associated β-gal staining and decreased protein levels of two cell senescence markers, p53 and p21. [i]BMAL1[/i] knockdown diminishes this effect, and BMAL1 overexpression abolishes [[STUB1]]'s effect on cell senescence. In summary, the results of our work reveal that the E3 ubiquitin ligase [[STUB1]] ubiquitinates and degrades its substrate BMAL1 and thereby alleviates hydrogen peroxide-induced cell senescence.

|keywords=* E3 ubiquitin ligase
* STIP1 homology and U-box-containing protein 1 (STUB1)
* brain and muscle ARNT-like 1 (BMAL1, ARNTL, MOP3)
* cell cycle regulation
* circadian clock
* hydrogen peroxide
* proteasome
* protein degradation
* senescence
* ubiquitylation (ubiquitination)
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7135990
}}
{{medline-entry
|title=Deficiency of Bmal1 disrupts the diurnal rhythm of haemostasis.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30610898
|abstract=Mice deficient in the circadian clock gene BMAL1 (Brain and Muscle [[ARNT]]-like protein-1) exhibit a hypercoagulable state and an enhanced arterial and venous thrombogenicity, which aggravates with age. We investigated the effect of BMAL1 deficiency in mice at a different age on the diurnal rhythm of factors involved in coagulation and fibrinolysis. Hepatic, cardiac and brain tissues were isolated from 10- and 25-weeks-old Bmal1-deficient (BMAL1 ) and wild-type (BMAL1 ) mice at ZT2 and at ZT14 to analyze the mRNA expression level of genes involved in coagulation and fibrinolysis. Body weight and brain weight were significantly lower in all BMAL1  versus BMAL1  mice. Bmal1 deficiency disturbed the diurnal rhythm of plasminogen activator inhibitor-1 (PAI-1) in liver and plasma, but not in cardiac or brain tissues. BMAL1  livers showed diurnal fluctuations in factor (F)VII, FVII, protein S and anti-thrombin gene expression, which were not observed in BMAL1  tissues. Interestingly, tissue plasminogen activator (t-PA) expression was significantly upregulated in all BMAL1  versus BMAL1  brains at both time points. Plasma t-PA-PAI-1 complex levels were however similar for all groups. Bmal1 deficiency affected the biphasic rhythm of coagulation and fibrinolysis factors predominantly in the liver. In the brain, Bmal1-dependent control of t-PA gene expression was documented for the first time.
|mesh-terms=* ARNTL Transcription Factors
* Animals
* Blood Cell Count
* Blood-Brain Barrier
* Body Composition
* Brain
* Circadian Rhythm
* Hemostasis
* Male
* Mice
* Mice, Inbred C57BL
* Myocardium
* Plasminogen Activator Inhibitor 1
* Tissue Plasminogen Activator
|keywords=* Aging
* Bmal1
* Coagulation
* Diurnal rhythm
* Fibrinolysis
* Haemostasis
|full-text-url=https://sci-hub.do/10.1016/j.exger.2018.12.017
}}
{{medline-entry
|title=Insulin-like growth factor-1 acts as a zeitgeber on hypothalamic circadian clock gene expression via glycogen synthase kinase-3β signaling.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30217816
|abstract=Brain and muscle [[ARNT]]-like protein-1 (BMAL-1) is an important component of the cellular circadian clock. Proteins such as epidermal ([[EGF]]) or nerve growth factor ([[NGF]]) affect the cellular clock via extracellular signal-regulated kinases-1/2 (ERK-1/2) in NIH3T3 or neuronal stem cells, but no such data are available for the insulin-like growth factor-1 (IGF-1). The hypothalamus expresses receptors for all three growth factors, acts as a central circadian pacemaker, and releases hormones in a circadian fashion. However, little is known about growth factor-induced modulation of clock gene activity in hypothalamic cells. Here, we investigated effects of IGF-1, [[EGF]], or [[NGF]] on the [i]Bmal-1[/i] promoter in two hypothalamic cell lines. We found that only IGF-1 but not [[EGF]] or [[NGF]] enhanced activity of the [i]Bmal-1[/i] promoter. Inhibition of ERK-1/2 activity did not affect IGF-1-induced [i]Bmal-1[/i] promoter activation and all three growth factors similarly phosphorylated ERK-1/2, questioning a role for ERK-1/2 in controlling [i]BMAL-1[/i] promoter activity. Of note, only IGF-1 induced sustained phosphorylation of glycogen synthase kinase-3β (GSK-3β). Moreover, the GSK-3β inhibitor lithium or siRNA-mediated GSK-3β knockdown diminished the effects of IGF-1 on the [i]Bmal-1[/i] promoter. When IGF-1 was used in the context of temperature cycles entraining hypothalamic clock gene expression to a 24-h rhythm, it shifted the phase of [i]Bmal-1[/i] promoter activity, indicating that IGF-1 functions as a zeitgeber for cellular hypothalamic circadian clocks. Our results reveal that IGF-1 regulates clock gene expression and that GSK-3β but not ERK-1/2 is required for the IGF-1-mediated regulation of the [i]Bmal-1[/i] promoter in hypothalamic cells.
|mesh-terms=* ARNTL Transcription Factors
* Animals
* Circadian Clocks
* Gene Expression Regulation
* Glycogen Synthase Kinase 3 beta
* Hypothalamus
* Insulin-Like Growth Factor I
* Mice
* NIH 3T3 Cells
* Phosphorylation
* Promoter Regions, Genetic
* Signal Transduction
|keywords=* aging
* circadian clock
* glycogen synthase kinase 3 (GSK-3)
* growth factor
* insulin-like growth factor (IGF)
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6222112
}}
{{medline-entry
|title=Aging and chromatoid body assembly: Are these two physiological events linked?
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/29958504
|abstract=The chromatoid body is a cytoplasmic male germ cell structure that plays a role in the regulation of mRNA transcription during spermatogenesis. A proteomic analysis of this structure has identified the presence of its classic molecular markers (MVH and MIWI), as well as a significant number of transient proteins. Circadian locomotor output cycles protein kaput ([[CLOCK]]) and brain and muscle [[ARNT]]-like 1 (BMAL1), which are molecular components of the circadian clock, are likely located in the chromatoid body in a transient fashion. This study sought to determine whether aging produces morphological changes in the chromatoid bodies of round spermatids similar to those previously observed in BMAL1 knockout mice. A sample of 30 male mice was divided into three groups: juvenile mice (45 days old), adult mice (120 days old), and old mice ( 180 days old). Aging was confirmed by viability and sperm count analyses and testosterone dosage. Squash slides prepared with fragments of seminiferous tubules were immunostained for MVH, MIWI, BMAL1, and [[CLOCK]] detection. In juvenile and adult specimens, single round chromatoid bodies were observed using MVH/BMAL1 and MIWI/[[CLOCK]] immunostaining. In old specimens, many chromatoid bodies displayed changes in number and morphology, as well as an increase in the interactions between MVH and BMAL1; MIWI and [[CLOCK]]. Changes in chromatoid body morphology increased interactions between the proteins analyzed herein, and decreased amounts of these proteins in seminiferous tubules of older mice may indicate that aging influences the assembly and physiology of chromatoid bodies, which may, in turn, affect fertility. Impact statement The results discussed in this paper indicate that aging compromises the structure and physiology of chromatoid bodies (CBs) in post-meiotic male cells. Since CB is a fundamental structure for the differentiation of the mature male germ cell it is possible that this imbalance in CB physiology may play a role in the reduction of fertility in older men. It is important to note that not only the classic CB markers (such as the MIWI and MVH proteins) were used to showcase the structural changes in the CBs but also the main components of circadian cycle control (the [[CLOCK]] and BMAL1 proteins), indicating that the reduction of circadian control in aged males may contribute to these changes in CBs as well. Therefore, it is intriguing to evaluate the hypothesis that controlling these physiological/structural changes in CBs may be a way of delaying the effects of aging in males.
|mesh-terms=* ARNTL Transcription Factors
* Age Factors
* Aging
* Animals
* Argonaute Proteins
* CLOCK Proteins
* Cytoplasmic Granules
* DEAD-box RNA Helicases
* Male
* Mice
* Microscopy, Fluorescence
* Nucleoproteins
* Spermatids
|keywords=* Aging
* chromatoid body
* fertility
* spermatogenesis
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6108056
}}
{{medline-entry
|title=Deficiency of circadian clock protein BMAL1 in mice results in a low bone mass phenotype.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/26789548
|abstract=The circadian clock is an endogenous time keeping system that controls the physiology and behavior of many organisms. The transcription factor Brain and Muscle [[ARNT]]-like Protein 1 (BMAL1) is a component of the circadian clock and necessary for clock function. Bmal1(-/-) mice display accelerated aging and many accompanying age associated pathologies. Here, we report that mice deficient for BMAL1 have a low bone mass phenotype that is absent at birth and progressively worsens over their lifespan. Accelerated aging of these mice is associated with the formation of bony bridges occurring across the metaphysis to the epiphysis, resulting in shorter long bones. Using micro-computed tomography we show that Bmal1(-/-) mice have reductions in cortical and trabecular bone volume and other micro-structural parameters and a lower bone mineral density. Histology shows a deficiency of BMAL1 results in a reduced number of active osteoblasts and osteocytes in vivo. Isolation of bone marrow derived mesenchymal stem cells from Bmal1(-/-) mice demonstrate a reduced ability to differentiate into osteoblasts in vitro, which likely explains the observed reductions in osteoblasts and osteocytes, and may contribute to the observed osteopenia. Our data support the role of the circadian clock in the regulation of bone homeostasis and shows that BMAL1 deficiency results in a low bone mass phenotype. 
|mesh-terms=* ARNTL Transcription Factors
* Animals
* Bone Density
* Bone and Bones
* Cell Count
* Cell Differentiation
* Circadian Clocks
* Epiphyses
* Growth Plate
* Mice, Inbred C57BL
* Organ Size
* Osteocytes
* Phenotype
* X-Ray Microtomography
|keywords=* Aging
* Biological clock
* Mesenchymal stem cell
* Osteoblast
* Osteogenesis, bone
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4755907
}}
{{medline-entry
|title=Circadian clocks govern calorie restriction-mediated life span extension through BMAL1- and IGF-1-dependent mechanisms.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/26700733
|abstract=Calorie restriction (CR) increases longevity in many species by unknown mechanisms. The circadian clock was proposed as a potential mediator of CR. Deficiency of the core component of the circadian clock-transcriptional factor BMAL1 (brain and muscle [[ARNT]] [aryl hydrocarbon receptor nuclear translocator]-like protein 1)-results in accelerated aging. Here we investigated the role of BMAL1 in mechanisms of CR. The 30% CR diet increased the life span of wild-type (WT) mice by 20% compared to mice on anad libitum(AL) diet but failed to increase life span ofBmal1(-/-)mice. BMAL1 deficiency impaired CR-mediated changes in the plasma levels of IGF-1 and insulin. We detected a statistically significantly reduction of IGF-1 in CRvs.AL by 50 to 70% in WT mice at several daily time points tested, while inBmal1(-/-)the reduction was not significant. Insulin levels in WT were reduced by 5 to 9%, whileBmal1(-/-)induced it by 10 to 35% at all time points tested. CR up-regulated the daily average expression ofBmal1(by 150%) and its downstream target genesPeriods(by 470% forPer1and by 130% forPer2). We propose that BMAL1 is an important mediator of CR, and activation of BMAL1 might link CR mechanisms with biologic clocks.-Patel, S. A., Chaudhari, A., Gupta, R., Velingkaar, N., Kondratov, R. V. Circadian clocks govern calorie restriction-mediated life span extension through BMAL1- and IGF-1-dependent mechanisms. 
|mesh-terms=* ARNTL Transcription Factors
* Animals
* Blood Glucose
* Blotting, Western
* Body Weight
* Caloric Restriction
* Circadian Clocks
* Female
* Insulin
* Insulin-Like Growth Factor I
* Life Expectancy
* Longevity
* Male
* Mice, Inbred C57BL
* Mice, Knockout
* Motor Activity
* Reverse Transcriptase Polymerase Chain Reaction
* Signal Transduction
* Time Factors
|keywords=* aging
* food anticipation
* gene expression
* glucose
* insulin
* transcription
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4799504
}}
{{medline-entry
|title=Whole blood thrombin generation in Bmal1-deficient mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/24740693
|abstract=The Calibrated Automated Thrombogram (CAT) assay that measures thrombin generation ([[TG]]) in platelet-poor and -rich plasma, is increasingly being recognised as a more sensitive tool to determine the overall function of the haemostatic system. We developed a method enabling the measurement of [[TG]] in a small aliquot of blood. The objective was to validate this assay in mouse blood and to examine the rate and extent of [[TG]] in a mouse model of premature aging. [[TG]] was assayed in blood from 20- to 28-week-old brain and muscle [[ARNT]]-like protein-1 (Bmal1)-deficient (knockout, KO) mice and wild-type (WT) littermates. Bmal1-KO mice are known to display symptoms of premature aging. [[TG]] was initiated by adding calcium, tissue factor and a thrombin specific substrate. After [[TG]], the samples were prepared for scanning electron microscopy (SEM). The intra-assay variations (%) in mouse blood of the endogenous thrombin potential (ETP), peak height, lag time, time-to-peak and velocity index were 10% or less (n=24). We found that Bmal1-KO mice have a significantly (p<0.001) higher ETP (437 ± 7 nM.min; mean ± SD, n=7) when compared with WT mice (ETP=220 ± 45 nM.min; mean ± SD, n=5). The peak heights also differed significantly (p=0.027). By applying SEM we found that Bmal1 deficient mice display a denser fibrin network with smaller pores compared to WT mice. In conclusion, the whole blood [[TG]] assay in mice revealed to be reproducible. As a proof-of-principle we have shown that the whole blood [[TG]] assay is capable of detecting a prothrombotic phenotype in Bmal1-KO mice. 
|mesh-terms=* ARNTL Transcription Factors
* Aging, Premature
* Animals
* Blood Coagulation
* Blood Coagulation Tests
* Disease Models, Animal
* Fibrin
* Genetic Predisposition to Disease
* Male
* Mice, Inbred C57BL
* Mice, Knockout
* Microscopy, Electron, Scanning
* Phenotype
* Predictive Value of Tests
* Reproducibility of Results
* Thrombin
* Thrombosis
|keywords=* Bmal1-KO mice
* Thrombin generation
* aging
|full-text-url=https://sci-hub.do/10.1160/TH13-11-0910
}}
{{medline-entry
|title=Age-related BMAL1 change affects mouse bone marrow stromal cell proliferation and osteo-differentiation potential.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/22457671
|abstract=Aging people's bone regeneration potential is always impaired. Bone marrow stromal cells (MSCs) contain progenitors of osteoblasts. Donor age may affect MSCs' proliferation and differentiation potential, but the genomic base is still unknown. Due to recent research's indication that a core circadian component, brain and muscle [[ARNT]]-like 1 protein (BMAL1), has a role in premature aging, we investigated the normal aging mechanism in mice with their MSCs and Bmal1 gene/protein level. 1, 6 and 16 month old C57BL/6 mice were used and the bone marrow stromal cells were gained and cultured at early passage. Bmal1 gene and protein level were detected in these cells. Marrow stromal cells were also induced to differentiate to osteoblasts or adipocytes. Three groups of mice MSCs were compared on proliferation by flow cytometry, on cell senescence by SA-β-gal expression and after osteo-induction on osteogenic potential by the expression of osterix (Osx), alkaline phosphatase (ALP) and osteocalcin (OCN). Bmal1 gene and protein level as well as S-phase fraction of the cell cycle decreased in MSCs along with the aging process. At the same time, SA-β-gal  levels increased, especially in the aged mice MSCs. When induced to be osteogenic, Osx gene expression and ALP activity declined in the mid-age and aged mice MSCs, while OCN protein secretion deteriorated in the aged mice MSCs. These findings demonstrate that mouse MSCs changed with their proliferation and osteo-differentiation abilities at different aging stages, and that Bmal1 is related to the normal aging process in MSCs.

|keywords=* aging
* bone marrow stromal cells
* brain and muscle ARNT-like 1 protein
* differentiation
* proliferation
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3309433
}}
{{medline-entry
|title=Disruption of hypoxia-inducible factor 1 in adipocytes improves insulin sensitivity and decreases adiposity in high-fat diet-fed mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/21873554
|abstract=Obesity, insulin resistance, and type 2 diabetes form a tightly correlated cluster of metabolic disorders in which adipose is one of the first affected tissues. The role of hypoxia and hypoxia-inducible factor 1 (HIF1) in the development of high-fat diet (HFD)-induced obesity and insulin resistance was investigated using animal models. Mice with adipocyte-specific targeted disruption of the genes encoding the HIF1 obligatory subunits Hif1α or Arnt (Hif1β) were generated using an aP2-Cre transgene with the Cre/LoxP system. The mice were fed an HFD for 12 weeks and their metabolic phenotypes were determined. Gene expression patterns in adipose tissues were also determined by microarray and quantitative PCR. On an HFD, adipocyte-specific [[ARNT]] knockout mice and adipocyte-specific HIF1α knockout mice exhibit similar metabolic phenotypes, including reduced fat formation, protection from HFD-induced obesity, and insulin resistance compared with similarly fed wild-type controls. The cumulative food intake remained similar; however, the metabolic efficiency was lower in adipocyte-specific HIF1α knockout mice. Moreover, indirect calorimetry revealed respiratory exchange ratios were reduced in adipocyte-specific HIF1α knockout mice. Hyperinsulinemic-euglycemic clamp studies demonstrated that targeted disruption of HIF1α in adipocytes enhanced whole-body insulin sensitivity. The improvement of insulin resistance is associated with decreased expression of Socs3 and induction of adiponectin. Inhibition of HIF1 in adipose tissue ameliorates obesity and insulin resistance. This study reveals that HIF1 could provide a novel potential therapeutic target for obesity and type 2 diabetes.
|mesh-terms=* Adipocytes
* Adipose Tissue, Brown
* Adipose Tissue, White
* Adiposity
* Aging
* Animals
* Aryl Hydrocarbon Receptor Nuclear Translocator
* Dietary Fats
* Gene Expression Regulation
* Glucose Clamp Technique
* Hypoxia-Inducible Factor 1, alpha Subunit
* Insulin Resistance
* Liver
* Mice
* Mice, Knockout
* Muscle, Skeletal
* Oxygen Consumption

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3178277
}}
{{medline-entry
|title=Progression of the prothrombotic state in aging Bmal1-deficient mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/21799179
|abstract=The goal of this study was to examine the functional relationship between aging endothelium and thrombogenicity in a mouse model of premature aging. Coagulation tests and factors, blood cell counts, aorta endothelial function, aorta gene expression, and FeCl(3)-induced thrombosis in mesenteric blood vessels were analyzed in 10- to 30-week-old brain and muscle [[ARNT]]-like protein-1 (Bmal1)-deficient (knockout [KO]) mice and wild-type littermates. Ten-week-old KO mice manifested shortened prothrombin times (9.7 versus 11.3 seconds in wild-type) and elevated plasma fibrinogen (264 versus 172 mg/dL). At 30 weeks, factor VII (198% versus 149%), and platelet counts (2049 versus 1354 K/μL) were increased in KO mice. Gene deficiency reduced the vasoactive nitric oxide production at 10 and 30 weeks and tended to reduce and increase the protein expression of thrombomodulin and von Willebrand factor, respectively, with aging. Shortened venular and arteriolar occlusion times on FeCl(3)-induced injury in 10-week-old KO mice confirmed higher thrombogenicity, culminating in priapism, observed in 60% of 25- to 30-week-old KO males. Endothelial dysfunction and a hypercoagulable state cause early arterial and venous thrombogenicity in Bmal1 KO mice. With aging, progressive endothelial dysfunction, rising platelet counts, and high factor VII further enhance thrombogenicity, provoking priapism.
|mesh-terms=* ARNTL Transcription Factors
* Aging
* Aging, Premature
* Animals
* Disease Models, Animal
* Disease Progression
* Endothelium, Vascular
* Fibrinogen
* Male
* Mice
* Mice, Knockout
* Platelet Count
* Prothrombin Time
* Thrombomodulin
* Thrombosis
* von Willebrand Factor

|full-text-url=https://sci-hub.do/10.1161/ATVBAHA.111.229062
}}
{{medline-entry
|title=Early aging and age-related pathologies in mice deficient in BMAL1, the core componentof the circadian clock.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/16847346
|abstract=Mice deficient in the circadian transcription factor BMAL1 (brain and muscle [[ARNT]]-like protein) have impaired circadian behavior and demonstrate loss of rhythmicity in the expression of target genes. Here we report that Bmal1(-/-) mice have reduced lifespans and display various symptoms of premature aging including sarcopenia, cataracts, less subcutaneous fat, organ shrinkage, and others. The early aging phenotype correlates with increased levels of reactive oxygen species in some tissues of the Bmal1(-/- )animals. These findings, together with data on CLOCK/BMAL1-dependent control of stress responses, may provide a mechanistic explanation for the early onset of age-related pathologies in the absence of BMAL1.
|mesh-terms=* ARNTL Transcription Factors
* Adipose Tissue
* Aging
* Aging, Premature
* Animals
* Animals, Newborn
* Basic Helix-Loop-Helix Transcription Factors
* Body Weight
* Circadian Rhythm
* Female
* Gene Expression Regulation
* Male
* Mice
* Mice, Inbred C57BL
* Mice, Knockout
* Muscle, Skeletal
* Organ Size
* Reactive Oxygen Species

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1522083
}}
{{medline-entry
|title=Expression of basic helix-loop-helix/PAS genes in the mouse suprachiasmatic nucleus.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/10077321
|abstract=The suprachiasmatic nuclei contain a circadian clock that drives rhythmicity in physiology and behavior. In mice, mutation of the Clock gene produces abnormal circadian behavior [Vitaterna M. H. et al. (1994) Science 264, 715-725]. The Clock gene encodes a protein containing basic helix-loop-helix and PAS (PER-[[ARNT]]-SIM) domains [King D. P. et al. (1997) Cell 89, 641-653]. The PAS domain may be an important structural feature of a subset of genes involved in photoreception and circadian rhythmicity. The expression and regulation of messenger RNAs encoding eight members of the basic helix-loop-helix/PAS protein superfamily were examined by in situ hybridization. Six of the genes studied (aryl hydrocarbon receptor nuclear transporter, aryl hydrocarbon receptor nuclear transporter-2, Clock, endothelial PAS-containing protein, hypoxia-inducible factor-1alpha and steroid receptor coactivator-1) were expressed in the suprachiasmatic nucleus of adult and neonatal mice. No evidence for rhythmicity of expression was observed when comparing brains collected early in the subjective day (circadian time 3) with those collected early in subjective night (circadian time 15). Neuronal PAS-containing protein-1 messenger RNA was expressed in the suprachiasmatic nucleus of adult (but not neonatal) mice, and a low-amplitude rhythm of neuronal PAS-containing protein-1 gene expression was detected in the suprachiasmatic nucleus. Neuronal PAS-containing protein-2 messenger RNA was not detected in adult or neonatal suprachiasmatic nucleus. Exposure to light at night (30 or 180 min of light, beginning at circadian time 15) did not alter the expression of any of the genes studied. The expression of multiple members of the basic helix-loop-helix/PAS family in the suprachiasmatic nucleus suggests a rich array of potential interactions relevant to the regulation of the suprachiasmatic circadian clock.
|mesh-terms=* Aging
* Animals
* Animals, Newborn
* Basic Helix-Loop-Helix Transcription Factors
* Gene Expression
* Helix-Loop-Helix Motifs
* Male
* Mice
* Mice, Inbred C57BL
* Suprachiasmatic Nucleus
* Trans-Activators

|full-text-url=https://sci-hub.do/10.1016/s0306-4522(98)00325-x
}}